Evidence map›Paper›PMID 34358446›Full record

ArticleMolecular cell2021

Molecular basis for substrate recruitment to the PRMT5 methylosome.

Kathleen M Mulvaney, Christa Blomquist, Nischal Acharya, Ruitong Li, Matthew J Ranaghan, Meghan O'Keefe, Diego J Rodriguez, Michael J Young, Devishi Kesar, Debjani Pal and 18 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
59citing papers in PubMed, 1 pooled it
4.0field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

59 citing papers in PubMed, 1 synthesis or guideline pooled it, 83 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors at 4 institutions in 1 country.

Kathleen M MulvaneyBroad Institute, Cambridge, MA, USA.
Christa BlomquistBroad Institute, Cambridge, MA, USA.
Nischal AcharyaBroad Institute, Cambridge, MA, USA.
Ruitong LiBroad Institute, Cambridge, MA, USA.
Matthew J RanaghanCenter for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
Meghan O'KeefeCenter for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
Diego J RodriguezBroad Institute, Cambridge, MA, USA.
Michael J YoungBroad Institute, Cambridge, MA, USA.
Devishi KesarBroad Institute, Cambridge, MA, USA.
Debjani PalBroad Institute, Cambridge, MA, USA.
Matthew StokesCell Signaling Technologies, Danvers, MA, USA.
Alissa J NelsonCell Signaling Technologies, Danvers, MA, USA.
Sidharth S JainBroad Institute, Cambridge, MA, USA.
Annan YangTango Therapeutics, Cambridge, MA, USA.
Zachary Mullin-BernsteinBroad Institute, Cambridge, MA, USA.
Josie ColumbusBroad Institute, Cambridge, MA, USA.
Fazli K BozalBroad Institute, Cambridge, MA, USA.
Adam SkepnerCenter for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
Donald RaymondCenter for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
Salvatore LaRussaCenter for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
David C McKinneyCenter for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
Yelena FreyzonBroad Institute, Cambridge, MA, USA.
Yossef BaidiBroad Institute, Cambridge, MA, USA.
Dale PorterBroad Institute, Cambridge, MA, USA; Cedilla Therapeutics, Cambridge, MA, USA.
Andrew J AguirreBroad Institute, Cambridge, MA, USA; Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Alessandra IanariBroad Institute, Cambridge, MA, USA.
Brian McMillanCenter for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA; Tango Therapeutics, Cambridge, MA, USA.
William R SellersBroad Institute, Cambridge, MA, USA; Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Electronic address: wsellers@broadinstitute.org.
Broad Institute · USCell Signaling Technology (United States) · USDana-Farber Cancer Institute · USTango Therapeutics (United States) · US

Funding

The function of the PRMT5 methylosome in MTAP deleted cancersR01CA233626 · NCI · BROAD INSTITUTE, INC. · PI Andrew James Aguirre, WILLIAM R SELLERS · 2019 to 2026
$2.9M
The novel PRMT5-substrate adaptor interface provides a therapeutic target in MTAP null tumorsF32CA232543 · NCI · BROAD INSTITUTE, INC. · PI MULVANEY, KATHLEEN · 2018 to 2021
$221k
NCI NIH HHS F32 CA232543NCI NIH HHS R01 CA233626
6 · The paper itself

Abstract

PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5.

Indexed as

AnimalsCell Line, TumorCytoplasmFemaleHCT116 CellsHEK293 CellsHistonesHumansIntracellular Signaling Peptides and ProteinsIon ChannelsMaleMethylationMiceMice, NudeNuclear ProteinsPeptidesCLNS1A protein, humanCOPRS protein, humanHistonesIntracellular Signaling Peptides and ProteinsIon ChannelsNuclear ProteinsPeptidesPRMT2 protein, humanPRMT5 protein, humanProtein-Arginine N-MethyltransferasesProtein Serine-Threonine KinasesRIOK1 protein, humanarginine methylationCDKN2ACOPR5histoneMTAPpIClnPRMT5RIOK1Sm proteinsplicing

Identifiers

PMID34358446
PMCPMC9016627
OpenAlexW3190829687

What OpenQuestion holds

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Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.